Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?

Abstract

The discovery of the glial-lymphatic or glymphatic fluid clearance pathway in the rodent brain led researchers to search for a parallel system in humans and to question the implications of this pathway in neurodegenerative diseases. Magnetic resonance imaging studies revealed that several features of the glymphatic system may be present in humans. In both rodents and humans, this pathway promotes the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF) through the arterial perivascular spaces into the brain parenchyma. This process is facilitated in part by aquaporin-4 (AQP4) water channels located primarily on astrocytic end feet that abut cerebral endothelial cells of the blood brain barrier. Decreased expression or mislocalization of AQP4 from astrocytic end feet results in decreased interstitial flow, thereby, promoting accumulation of extracellular waste products like hyperphosphorylated Tau (pTau). Accumulation of pTau is a neuropathological hallmark in Alzheimer's disease (AD) and is accompanied by mislocalization of APQ4 from astrocyte end feet to the cell body. HIV infection shares many neuropathological characteristics with AD. Similar to AD, HIV infection of the CNS contributes to abnormal aging with altered AQP4 localization, accumulation of pTau and chronic neuroinflammation. Up to 30% of people with HIV (PWH) suffer from HIV-associated neurocognitive disorders (HAND), and changes in AQP4 may be clinically important as a contributor to cognitive disturbances. In this review, we provide an overview and discussion of the potential contributions of NeuroHIV to glymphatic system functions by focusing on astrocytes and AQP4. Although HAND encompasses a wide range of neurocognitive impairments and levels of neuroinflammation vary among and within PWH, the potential contribution of disruption in AQP4 may be clinically important in some cases. In this review we discuss implications for possible AQP4 disruption on NeuroHIV disease trajectory and how HIV may influence AQP4 function.

Keywords: NeuroHIV; astrocyte; brain; glymphatic system; neuroinflammation.

Figure 1

The neurovascular unit. The neurovascular unit is composed of neurons, astrocytes, cerebral endothelial cells, smooth muscle myocytes, pericytes, and matrix components.

Figure 2

Glymphatic system. The glymphatic system is comprised of astrocytes, aquaporin 4 water channels and cerebral perivascular spaces. Aquaporin 4 water channels, located on astrocytic end feet facilitate movement of water to for the exchange of interstitial fluid and cerebrospinal fluid and to propel extracellular contents such as cellular debris, abnormal proteins and waste products through brain parenchyma for clearance. The glymphatic system also transports glucose, lipids, amino acids, growth factors and neuromodulators through-out the brain. In health, these components can be cleared more efficiently primarily during sleep.

Figure 3

Astrocyte subtypes. Astrocytes can be classified into numerous subtypes based on morphology, active state and anatomical location. Astrocytes are stimulated to become reactive by challenges such as inflammation or ischemia. The A1 subtype is induced by inflammation, is generally considered neurotoxic and produces inflammatory cytokines and pro-apoptotic factors. On the other hand, the A2 subtype is induced by ischemic conditions, such as stroke and releases neurotrophic factors and is considered to be neuroprotective.

Figure 4

Impaired glymphatic system. After injury or during CNS diseases with a neuroinflammatory component such as HIV infection, the glymphatic system functions less efficiently. This may be due in part to increased inflammatory factors or to the production of viral proteins by HIV infected cells. In this scenario, mislocalization of AQP4 from astrocyte end feet to the cell body and/or reduced expression of AQP4 may lead to accumulation of toxic waste products such as hyperphosphorylated Tau.